rs16030

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001127222.2(CACNA1A):c.3861T>C(p.Phe1287=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.212 in 1,608,954 control chromosomes in the GnomAD database, including 37,769 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.18 ( 2720 hom., cov: 31)

Exomes 𝑓: 0.22 ( 35049 hom. )

Consequence

CACNA1A
NM_001127222.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.776

Variant links:

Genes affected

CACNA1A (HGNC:1388): (calcium voltage-gated channel subunit alpha1 A) Voltage-dependent calcium channels mediate the entry of calcium ions into excitable cells, and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, and gene expression. Calcium channels are multisubunit complexes composed of alpha-1, beta, alpha-2/delta, and gamma subunits. The channel activity is directed by the pore-forming alpha-1 subunit, whereas, the others act as auxiliary subunits regulating this activity. The distinctive properties of the calcium channel types are related primarily to the expression of a variety of alpha-1 isoforms, alpha-1A, B, C, D, E, and S. This gene encodes the alpha-1A subunit, which is predominantly expressed in neuronal tissue. Mutations in this gene are associated with 2 neurologic disorders, familial hemiplegic migraine and episodic ataxia 2. This gene also exhibits polymorphic variation due to (CAG)n-repeats. Multiple transcript variants encoding different isoforms have been found for this gene. In one set of transcript variants, the (CAG)n-repeats occur in the 3' UTR, and are not associated with any disease. But in another set of variants, an insertion extends the coding region to include the (CAG)n-repeats which encode a polyglutamine tract. Expansion of the (CAG)n-repeats from the normal 4-18 to 21-33 in the coding region is associated with spinocerebellar ataxia 6. [provided by RefSeq, Jul 2016]

CACNA1A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.53).

BP6

Variant 19-13277090-A-G is Benign according to our data. Variant chr19-13277090-A-G is described in ClinVar as [Benign]. Clinvar id is 128553.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-13277090-A-G is described in Lovd as [Benign]. Variant chr19-13277090-A-G is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=0.776 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.222 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1A	NM_001127222.2 linkuse as main transcript	c.3861T>C	p.Phe1287=	synonymous_variant	23/47	ENST00000360228.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1A	ENST00000360228.11 linkuse as main transcript	c.3861T>C	p.Phe1287=	synonymous_variant	23/47	1	NM_001127222.2		O00555-8

Frequencies

GnomAD3 genomes

AF:

0.177

AC:

26980

AN:

152008

Hom.:

2715

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0947

Gnomad AMI

AF:

0.0947

Gnomad AMR

AF:

0.164

Gnomad ASJ

AF:

0.182

Gnomad EAS

AF:

0.121

Gnomad SAS

AF:

0.220

Gnomad FIN

AF:

0.223

Gnomad MID

AF:

0.168

Gnomad NFE

AF:

0.225

Gnomad OTH

AF:

0.199

GnomAD3 exomes

AF:

0.195

AC:

48395

AN:

248210

Hom.:

5025

AF XY:

0.201

AC XY:

27073

AN XY:

134782

show subpopulations

Gnomad AFR exome

AF:

0.0946

Gnomad AMR exome

AF:

0.162

Gnomad ASJ exome

AF:

0.195

Gnomad EAS exome

AF:

0.111

Gnomad SAS exome

AF:

0.223

Gnomad FIN exome

AF:

0.218

Gnomad NFE exome

AF:

0.220

Gnomad OTH exome

AF:

0.208

GnomAD4 exome

AF:

0.216

AC:

314386

AN:

1456828

Hom.:

35049

Cov.:

AF XY:

0.217

AC XY:

157645

AN XY:

724870

show subpopulations

Gnomad4 AFR exome

AF:

0.0891

Gnomad4 AMR exome

AF:

0.169

Gnomad4 ASJ exome

AF:

0.194

Gnomad4 EAS exome

AF:

0.126

Gnomad4 SAS exome

AF:

0.226

Gnomad4 FIN exome

AF:

0.218

Gnomad4 NFE exome

AF:

0.225

Gnomad4 OTH exome

AF:

0.204

GnomAD4 genome

AF:

0.178

AC:

27010

AN:

152126

Hom.:

2720

Cov.:

AF XY:

0.177

AC XY:

13150

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.0948

Gnomad4 AMR

AF:

0.164

Gnomad4 ASJ

AF:

0.182

Gnomad4 EAS

AF:

0.121

Gnomad4 SAS

AF:

0.221

Gnomad4 FIN

AF:

0.223

Gnomad4 NFE

AF:

0.225

Gnomad4 OTH

AF:

0.202

Alfa

AF:

0.215

Hom.:

6238

Bravo

AF:

0.169

Asia WGS

AF:

0.184

AC:

636

AN:

3478

EpiCase

AF:

0.220

EpiControl

AF:

0.221

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 07, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 03, 2021	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 09, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.53

Cadd

Benign

9.0

Dann

Benign

0.73

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over